Wilson disease is an inherited neurometabolic condition afflicting children and young adults that is characterized by the presence of extensive deposits of copper in tissues, mainly in the liver and brain. If no treatment is rendered, the disease usually results in death.1 The goals of the treatment of Wilson disease are to prevent the onset of symptoms in asymptomatic people, to delay clinical deterioration in affected individuals, and, in cases of acute-on-chronic hepatitis, possibly to save lives. The doses of chelating agents or zinc salts administered to asymptomatic individuals should be smaller than those given to persons with symptomatic disease. Liver transplant should be considered immediately for individuals with acute-on-chronic liver failure or end-stage liver disease that is refractory to medications, whereas symptomatic patients can be managed with chelators or a combination of chelators and zinc. Lifelong monitoring is necessary to ensure compliance with treatment, assess its efficacy, and detect the potential emergence of side effects.2

The primary therapy for Wilson disease consists of chelating agents and drugs that prevent the gastrointestinal tract from absorbing copper. The symptoms of parkinsonism, dystonia, and seizures are treated with anticholinergic agents, baclofen, gamma-aminobutyric acid (GABA) antagonists, and levodopa; seizures are treated with antiepileptics; and psychiatric symptoms are treated with neuroleptics. Additionally, lactulose, protein restriction, or both are used to treat hepatic encephalopathy.3

Anti-copper Drugs 

To treat Wilson disease, either zinc, which decreases the absorption of copper, or chelators (drugs that increase cupriuresis), or both are used to achieve a negative copper balance. Chelators include d-penicillamine, trientine, ammonium tetrathiomolybdate, and zinc, among others.4

Chelators

Penicillamine (Cuprimine®, Depen®) and trientine (Syprine®, trientine dihydrochloride) are among the chelator medications that have been approved for the treatment of Wilson disease. They act by binding to copper (chelation), increasing its urinary excretion.5 

Trientine is less likely to cause side effects than penicillamine. Fever, rash, and kidney or bone marrow abnormalities are possible side effects of penicillamine. Clinicians may advise patients to take a vitamin B6 supplement in conjunction with penicillamine because the latter may interfere with the functioning of vitamin B6. The initiation of chelator therapy in individuals with nervous system issues may exacerbate symptoms.6 

Zinc

Zinc acetate (Galzin®) is also approved for the treatment of Wilson disease. Zinc works by triggering the production of metallothionein and preventing the digestive system from absorbing copper, thereby removing accumulated copper and preventing it from reaccumulating. Zinc is frequently used as a maintenance therapy for asymptomatic patients, and in combination with chelators. The complete lack of adverse effects of zinc therapy is a significant benefit.5 

Ammonium Tetrathiomolybdate

In the intestines and blood, ammonium tetrathiomolybdate (TM) works by forming a tripartite complex with copper and protein that is neither toxic nor absorbable. When taken with meals, TM prevents the uptake of copper; when taken between meals, it binds copper in the plasma.4 

Liver Transplant

Orthotopic liver transplant should be considered for patients with acute liver failure and decompensated liver disease that is refractory to medical therapy. The underlying hepatic metabolic abnormalities in Wilson disease are cured by liver transplant.4 Because effective treatments for the metabolic abnormalities are available, liver transplant is not necessary except as a life-saving treatment for a patient with advanced cirrhosis or fulminant hepatic failure.2 

Diet and Nutrition

Foods rich in copper, such as shellfish, nuts, chocolate, mushrooms, and organ meats, should be eliminated from the diet, especially during the first year of treatment.4 These foods are permitted intermittently once copper levels have been stabilized at normal values.5

A water filtration system may be recommended, and the copper content of well water or water from water distribution systems to homes, which are frequently made of copper, should be evaluated. Copper containers should not be used for cooking.4

Physiotherapy and Occupational Therapy

Patients with the neurological form of Wilson disease benefit from occupational and physiotherapy, which can relieve ataxia, dystonia, and tremors and prevent the contractures that can arise from dystonia. The copper-chelating treatment can take up to 6 months to start working, hence occupational and physiotherapy are beneficial.7 

Specific Situations

Treatment of the Presymptomatic Patient

Presymptomatic patients are those in whom a clinical illness has not yet developed.8 A systematic review found that d-penicillamine and zinc were equally beneficial in presymptomatic individuals. However, adverse effects were more common with d-penicillamine. Some of the early adverse effects associated with d-penicillamine are fever, proteinuria, lymphadenopathy, rash, cytopenias. Some of the late adverse effects are lupus like syndrome, goodpasture syndrome, nephrotoxicity, elastosis perforans serpiginosa, and some very late adverse effects are myasthenia gravis and polymyositis.4 

Treatment of the Pregnant Patient 

Pregnant patients must continue receiving anticopper therapy to safeguard their health. Because of the teratogenic effects of penicillamine, many women used to discontinue their medication at a time when penicillamine was the only treatment available. As a result, serious illnesses developed in many of them, and some eventually died. Trientine and zinc are suggested alternatives.8 Acute liver failure may develop if medication is stopped during pregnancy. The dose of chelators such d-penicillamine and trientine can be lowered by 25% to 50%, whereas the dose of zinc can stay the same.4 

References

  1. Aggarwal A, Bhatt M. Advances in treatment of Wilson Disease. Tremor Other Hyperkinet Mov (N Y). 2018;8:525. doi:10.7916/D841881D 
  2. Rodriguez-Castro KI, Hevia-Urrutia FJ, Sturniolo GC. Wilson’s disease: a review of what we have learned. World J Hepatol. 2015;7(29):2859-2870. doi:10.4254/wjh.v7.i29.2859
  3. Gilroy RK. Wilson disease medication. Medscape. Updated February 14, 2019. Accessed September 11, 2022. 
  4. Patil M, Sheth KA, Krishnamurthy AC, Devarbhavi H. A review and current perspective on Wilson disease. J Clin Exp Hepatol. 2013;3(4):321-336. doi:10.1016/j.jceh.2013.06.002
  5. Treatment – Wilson disease. Wilson Disease Association. Accessed September 11, 2022.
  6. Treatment of Wilson disease. How do doctors treat Wilson disease?. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Accessed September 11, 2022.
  7. Chaudhry HS, Anilkumar AC. Wilson disease. StatPearls [Internet]. Updated May 8, 2022. Accessed September 11, 2022.
  8. Brewer GJ, Askari FK. Wilson’s disease: clinical management and therapy. J Hepatol. 2005;42 Suppl(1):S13-S21. doi:10.1016/j.jhep.2004.11.013

Reviewed by Debjyoti Talukdar, MD, on 9/26/2022.

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